Cholecystokinin (CCK) is a brain/gut neuropeptide which has been implicated in a number of central nervous system and gastrointestinal disease states [Reviews: J. A. Williams, Biomedical Research (1982), 3, 107; M. Albus, Prog. Neuro-Psychopharmacol & Biol. Psychiat. (1988), 12, p S5]. Cholecystokinin in the GI tract evokes contraction of gut smooth musculature [U. Scheurer et al, Am. J. Physiol. (1983, 244, G266], and functionally causes delayed gastric emptying, contraction of the gall bladder [E. Corazziari et al, Dig. Dis. & Sci. (1990), 35, 50], initiation of the gastrocolic reflex [R. F. Harvey and A. E. Read, The Lancet (1973), Sat. 6 Jan., p. 7793]. CCK plays an important physiologic role in pancreatic function and secretion. Abnormalities of CCK have been implicated in causing pancreatitis [C. Niederau et al, Gastroenterology (1985), 88, 1192]. Abnormalities of CCK function in the GI tract may be causitive in a number of GI motility disorders, including irritable bowel syndrome. Additionally, CCK acts as a physiologic opiate antagonist, and has been reported to be hyperalgesic, and to inhibit analgesia produced by opiates [P. L. Faris et al, Science (1983), 219, 310; N. S. Baber et al, Pain (1989), 39, 307].
Actions of CCK in the central nervous system have demonstrated a role for CCK in controling eating behavior (producing satiety) [G. P. Smith in Eating and Its Disorders (A. J. Stunkard & E. Stellar, Eds), (1984), pp. 67-75, Raven Press], in producing symptoms of panic disorder & other forms of anxiety [Trends in Pharmacol. Sci. (1990), 11, 271], and in modulating mesolimbic dopamine release [J. N. Crawley in Cholecystokinin Antagonists (R. Y. Wang R. Schoenfeld, eds., (1988), pp. 243-262, Alan R. Liss].
Finally, CCK and/or gastrin have been implicated as tumorgenic in a number of cancers, including cancers of the pancreas and the colon [S. A. Watson et al, GUT (1989, 30, 1447; B. R. Douglas et al, Cancer Research (1989), 49, 2438].
Thus, an antagonist to CCK at either the A-receptor subtype or the B-receptor subtype may be useful in the treatment of GI motility disorders (including irritable bowel syndrome), eating disorders where an anti-satiety effect is desired, panic-like anxiety, compulsive behavior and other CNS disorders.
U.S. Pat. No. 4,757,068 discloses a class of lactams and bicyclic lactams which are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal, central nervous and appetite regulatory systems of mammals. The compounds of this disclosure are structurally distinct from the present invention, i.e., they are bicyclic .beta.-lactam penicillin analogs having anti-bacterial activity. The compounds of this disclosure are distinct from the compounds of the present invention both in structure and utility.
U.S. Pat. No. 3,474,093 discloses pyrrolidinone, indolinone, cycloheptapyrrolone and cyclopentapyrrolone adducts of N-acyloxy-N-acylaminoacetanilides useful as hyperemic depressants, anti-convulsants and antiarrhythmic agents.